Lactation has favorable effects on cardiometabolic risk factor levels that persist after weaning, and may prevent the onset of type 2 diabetes mellitus (DM) in women in mid to late life. However, data are not available within the same study to directly link lactation to persistent changes in cardiometabolic risk factors (i.e., plasma lipids, glucose, insulin, overall and central adiposity) or biomarkers of insulin resistance as well as subsequent incidence of diabetes. We hypothesize that longer duration of lactation has lasting favorable effects on cardio- metabolic risk factors, biomarkers of insulin resistance (i.e., adipokines, endothelial function and inflammation) and visceral fat levels which lead to lower the risk of new onset diabetes in women during midlife, and the lactation-diabetes association does not differ by history of gestational diabetes mellitus (GDM). We propose an ancillary study to the Coronary Artery Risk Development in Young Adults (CARDIA) study, an ongoing, U.S. population-based, longitudinal study of 5,115 black and white women and men aged 18-30 yrs at enrollment (1985-1986) funded by the National Heart, Lung and Blood Institute (NHLBI). CARDIA recorded the natural history of child-bearing among 2,787 women, of whom 1,239 delivered 2,147 births since baseline (1986- 2006). Entering its 25th year, CARDIA will have measured cardiometabolic risk factors (fasting glucose, insulin, lipids, BMI, waist girth, blood pressure) up to 8 times since baseline (1986-2011), and performed oral glucose tolerance tests (OGTT) on individuals not known to be diabetic in 1995-1996 or 2005-2006, and is performing them again in 2010-2011. The goals of this study are to prospectively examine lactation duration and incidence of DM during a 25-year period (1986-2011), and assess whether lactation has lasting effects on cardio- metabolic risk factors, and biomarkers of insulin resistance and adiposity (adiponectin, IL-6, CRP, sICAM-1, leptin, sOB-R, TNF-1) that precede the onset of diabetes in women. We propose to assay biomarkers from stored sera collected in 1987-1988 (Year 2), 1995-1996 (Year 10), 2000-2001 (Year 15) and 2005-2006 (Year 20), and utilize other available biochemical and biomarker data to examine the changes from before to after pregnancy, and assess their relationship to subsequent incident DM in mid-life. We will also examine lactation duration and visceral fat in mid-life (Year 25, 2010-2011) via computed tomography. Finally, within the lactation-incident DM association we will examine history of GDM as an effect modifier, and changes in risk factors and biomarkers (prepregnancy to post-weaning) as mediators of the association. This study will be the first to examine "mediators" of the lactation-DM association by utilizing longitudinal biochemical data to preserve the temporality of the exposure (lactation) in relation to both biochemical changes as well as disease onset. The study may generate new insights and hypotheses for lactation's effects on metabolic pathways of diabetogenesis in women. Breastfeeding is a modifiable health behavior that may be translated into public health interventions for prevention of DM, including women with a history of GDM. PUBLIC HEALTH RELEVANCE: Breastfeeding may lower blood sugar levels and prevent women from developing diabetes years after pregnancy. Currently, there is no direct evidence that breastfeeding a child has lasting beneficial effects on risk factors that predict type 2 diabetes in women later in life. The proposed study will examine whether greater duration of breastfeeding protects women from developing diabetes and offer new insights on how breastfeeding may confer this protection.